Smoking is an important risk factor for cardiovascular disease, in particular for acute cardiovascular events such as myocardial infarction and sudden death. The mechanisms linking smoking to acute cardiovascular events are not known. Sympathetic and hemodynamic responses to cigarette smoking may be implicated. Previous studies have demonstrated that smoking increases heart rate and blood pressure and decreases muscle sympathetic nerve activity (SNA) in healthy subjects. However, the baroreflex response to the increased blood pressure during smoking may be inhibiting muscle SNA and blunting the tachycardia during smoking. Thus, in patients with baroreflex impairment (patients with hypertension, coronary artery disease or heart failure), smoking may trigger increases in muscle SNA and potentiated increases in heart rate and blood pressure. It is not known whether these populations, who are most vulnerable to acute cardiovascular events, have a differential response to cigarette smoking in comparison to healthy control subjects. We propose a series of investigations that promise mechanistic insight into the effects of cigarette smoking and the link between smoking and acute cardiovascular events. We will test the following specific hypotheses. 1) In young healthy subjects, cigarette smoking increases baroreflex independent skin SNA. Attenuation of the pressor effect of cigarette smoking (using intravenous nitroprusside infusion) is accompanied by increases in muscle SNA. 2) In patients with baroreflex impairment (elderly subjects and patients with overt cardiovascular disease), there is an increase in muscle SNA and catecholamines and a potentiation of the pressor and heart rate responses to smoking. 3) The effects of cigarette smoking on skin SNA and muscle SNA are mediated by nicotine. The integrity of the proposed hypotheses are supported by exciting preliminary data. These studies build on our broad experience in investigating both smoking and neural circulatory control, and should contribute significantly to understanding the mechanisms linking cigarette smoking to acute cardiovascular events.